Globally, the prevalence of hepatitis C virus (HCV) infection is 3% and constitutes a major public health burden. The true incidence of acute hepatitis C is unknown, although injecting drug users (IDUs) remain the population at greatest risk in the developed world. Currently, there is no effective HCV vaccine and only 15- 45% will spontaneously clear infection. Treatment in the acute stages of infection has been shown to be highly effective in non-IDU populations; however, few large studies have specifically addressed the question of the optimal treatment regimen in IDUs, many of whom are identified through asymptomatic seroconversion rather than symptomatic acute hepatitis. In the Australian Trial in Acute Hepatitis C (ATAHC) we demonstrated that subjects with recently acquired HCV infection (predominantly IDUs) can be successfully recruited, engaged and followed longitudinally. Overall, 167 individuals were enrolled and followed for up to 36 months. 76% of treatment eligible individuals (111/146) chose to commence treatment, including 37 individuals with HIV co- infection. Treatment success (defined as a sustained virological response, SVR) occurred in 55% of HCV monoinfected individuals, despite a high proportion of IDU (80%). SVR rates in the HIV/HCV group who were treated with combination therapy (peginterferon (PEG-IFN) and ribavirin) were higher at 74%. Both superinfection and reinfection with HCV were observed with possible impact on treatment response rates. Although demonstrating encouraging results, evaluation of strategies to further enhance treatment response rates are obviously required, particularly among IDUs with recently acquired infection. We propose to 1) evaluate the safety and efficacy of peginterferon (PEG-IFN) and ribavirin combination therapy versus PEG-IFN monotherapy among individuals with recent HCV infection 2) define the incidence, risk factors and natural history of HCV superinfection during treatment and its impact on virological response and 3) determine the prevalence and complexity of HCV protease and polymerase inhibitor mutations in recently acquired infection. The study will be identified as ATAHC II and will involve a randomized clinical trial design to evaluate the efficacy of combination versus monotherapy for 24 weeks. The same definition for newly acquired HCV infection will be used as in ATAHC to include individuals with an estimated duration of HCV infection up to 18 months. HIV/HCV coinfected individuals will be included. The primary endpoint of the study will be SVR. Secondary virological and safety secondary endpoints will be evaluated as will the impact of treatment on injection drug use, social stability and mental health. The prevalence of mixed infection at baseline and the incidence of superinfection in those without HCV suppression in the first 12 weeks of therapy will be assessed using both standard bulk sequencing and novel methods designed to detect the presence of low level HCV quasispecies. All individuals will be assessed for the presence of protease and polymerase resistance at screening using a panel of well characterised nucleic acid mutations in the NS3 / 4a and NS5 gene regions. PUBLIC HEALTH RELEVANCE: Hepatitis C virus infection represents a significant global health burden affecting over 3% of the world population. In developed countries the majority of incident cases occur in injection drug users (IDUs), many of who have significant other health and social issues, and in whom uptake of treatment is generally low. Whilst most treatment studies in recently acquired HCV infection have either excluded or enrolled few IDU participants, ATAHC 1 demonstrated the feasibility and successful engagement of IDUs in treatment for acute HCV. Determining the most effective treatment strategies to enhance outcomes in this population is now required to address this important public health burden.